Unmasking Kabuki syndrome: chromosome 8p22–8p23.1 duplication revealed by comparative genomic hybridization and BAC‐FISH

Abstract

Kabuki syndrome (KS) is a multiple congenital anomalies/mental retardation syndrome that heretofore has had an unknown etiology. Although several cases with KS features have been reported with different chromosome anomalies, none have had an autosomal cytogenetic aberration in common. We found an 8p22-8p23.1 duplication, using comparative genomic hybridization (CGH) in six unrelated patients diagnosed with KS. This observation was confirmed using BAC-FISH in all cases that delimited the duplicated region to approximately 3.5 Mb. No duplication of this region was found in two parents or 20 controls by either CGH or BAC-FISH. Two out of two mothers of KS patients and one out of 20 controls were found to have a heterozygous submicroscopic inversion at 8p23.1. As the six patients with KS represent different races, this duplication may represent a common etiologic basis for this disorder.

Failure to detect an 8p22–8p23.1 duplication in patients with Kabuki (Niikawa–Kuroki) syndrome

“…6 Contrary to these authors, we were not able to detect any 8p duplication in our series of 24 Caucasians KS selected according to the clinical Niikawa -Kuroki criteria. Similarly, Miyake et al 11 failed to find any duplication in 28 Asiatic patients with typical KS.…”

“…It is tempting to locate the breakpoints within the olfactory repeat region (ORRs) described by Giglio et al 16,17 However, it is possible that alternative LCRs can mediate rearrangements with subtle difference in the amount of deleted/duplicated material. 18 Based on FISH results obtained with the BAC RP11-122N11, Milunsky and Huang 6 suggested that a paracentric inversion may contribute to the occurrence of the 8p duplication. Using the same probe, Miyake et al 11 observed duplicated rather than inverted signals.…”

“…10 All patients were studied with BACs RP11-235F10, RP11-252K12, RP11-31B7 to detect the 8p duplication and BAC RP11-122N11 to study the paracentric inversion as described by Milunsky and Huang. 6 In addition, we used in six patients BACs RP11-11P7, RP11-140K14, RP11-112G9, RP11-92C1, RP11-23H1, and RP11-141K9 that are other clones included in the 8p22 -8p23.1 duplication. For each patient we counted 10 metaphases and 10 nuclei.…”

Kabuki syndrome: new ocular findings but no evidence of 8p22-p23.1 duplications in a clinically defined cohort

“…In 5/7 patients, this was confirmed using FISH with the same probes that defined the medial 8p23.1 (112G9) and distal 8p22 (92C1) boundaries of the duplications reported by Milunsky and Huang. 8 In each patient, the probes …”

“…We set out to review a series of clinically well-defined patients with KS to characterise their eye findings and to replicate the findings of Milunsky and Huang. 8 …”